The tumor necrosis factor receptor (TNFR) superfamily of proteins encompasses over a dozen members, most of which are type I transmembrane proteins, related by the presence of conserved cysteine-rich repeats (CRRs) in their N-terminal cysteine-rich domains (CRDs). Members of the TNFR superfamily include TNFRI (p55), TNFR2 (p75), TNFR3 (TNF-RP), Fas (also known as CD95 and Apol ), OX-40, 41 -BB, CD40, CD30, CD27, OPG, and p75 NGFR. (Smith et al. (1993) Cell 76:959-962; Armitage, R. J. (1994) Curr. Opin. Immunol. 6:407-413; Gruss et al. (1995) Blood 85, 3378-3404; Baker et al. (1996) Oncogene 12:1-9; and Simonet et al. (1997) Cell 89:309-319.) A TNFR superfamily member is typically a membrane-bound, trimeric or multimeric complex which is stabilized via intracysteine disulfide bonds that are formed between the cysteine-rich domains of individual subunit members (Banner et al. (1993) Cell 73:431-445). The proteins themselves do not have intrinsic catalytic activity, rather they function via association with other proteins to transduce cellular signals.
Most members of the TNFR superfamily recognize ligands that play critical roles as costimulators in immune responses. However, a subset of TNFR superfamily members have been determined to play a key role in the extracellular regulation of cell death. Induction of cell death requires a unique cytoplasmic motif which was originally identified in TNFRI and Fas and termed the "death domain" (Tartaglia et al. (1993) Cell 74:845-853 and Itoh and Nagata (1993) J. Biol. Chem. 268:10932-10937). Using the yeast two-hybrid method to clone genes encoding proteins that associate with the cytoplasmic domains of TNFRL or Fas, three dramatically different genes were identified (TRADD in Hsu et al (1995) Cell 81:495-504; FADD in Chinnaiyan et al. (1995) Cell 81:501-512; and RIP in Stanger et al. (1995) Cell 81:512-523). FADD was independently cloned with the same strategy, and termed MORT1 (Boldin et al. (1995) J. Biol. Chem. 270:7795-7798.) In fact, the only structural similarity between these proteins was the shared motif that has homology with the death domains of the TNFRI and Fas receptors. Death domains have recently been identified in a variety of proteins including, for example, the ankyrins, the Drosophila proteins PELLE and TUBE, DAP kinase, mouse myD88. (For review see Feinstein and Kimchi (1995) Trends. Biochem. Sci. 20:342-344; Golstein et al. (1995) Cell 81:185-186; Cleveland and Ihle (1995) Cell 81:479-482; and Hofinan and Tschopp (1995) FEBS Lett. 371:321-323). Moreover, the death domain has been implicated in protein:protein interactions between two proteins each containing such a domain. Such a death domain:death domain interaction is believed to be a crucial component of the cellular signal transduction pathways that lead to cell death, thus, implicating members of the TNFR superfamily in a wide range of signal transduction with appreciably diverse outcomes.
Aside from the membrane-bound forms of TNFR superfamily proteins that function as cellular signal transducers, a functional TNFR superfamily protein can also exist in a soluble form. Soluble versions of the superfamily bind cognate ligands and influence bioavailability. For instance, the osteoprotegerin protein family exists as a soluble protein (Simonet et al. (1997) Cell 89:309-319). Many soluble forms of the TNFR have been identified. Certain soluble TNFRs are elevated in disease states such as lupus and rheumatoid arthritis (Gabay et al. (1997) J. Rheumatol. 24(2):303-308). The soluble superfamily members lack the transmembrane domain characteristic of the majority of superfamily members due to either proteolytic cleavage or, at least in one instance, to alternative splicing (Gruss et al. (1995) Blood 85, 3378-3404).
Given the important role of proteins of the TNFR superfamily, including both soluble as well as membrane-bound family members, in a wide range of cellular signal transduction pathways, there exists a need for identifying novel members of the TNFR superfamily as well as for modulators of such molecules for use in regulating a variety of cellular responses.